Glycopyrronium bromide (also known as Glycopyrrolate bromide) is an antagonist of muscarinic receptor and used in the treatment of urinary incontinence (U.S. Pat. Nos. 6,214,792 and 5,919,760), sialorrhea (Tscheng, Z. Ann. Pharmacother, 2002), hyperhidrosis (US 20100276329), overactive bladder and for pre-surgery treatment. It is also an anticholinergic bronchodilator and used in the treatment of asthma and chronic obstructive pulmonary disease (COPD). Anti-muscarinic bronchodilators are generally considered to be more effective for COPD than for asthma.
Glycopyrrolate is a quaternary ammonium cation and was previously available as a bromine salt (U.S. Pat. No. 5,919,760), as an acetate salt (U.S. Pat. No. 5,976,499), as a tosylate salt (U.S. Pat. No. 9,006,462), as an oxalate salt (U.S. Pat. No. 5,403,588), as hydrogen sulfate salt (U.S. Pat. No. 5,460,820), or benzoate salt (U.S. Pat. No. 4,899,739), or as edisylate salt (U.S. Pat. No. 5,122,383). Glycopyrronium bromide has a short half-life of 0.6 to 1.2 hours.
Since pharmaceutical compositions require that the active pharmaceutical substance (API) has to be stable both chemically and physically, a number of studies to provide more suitable new forms of the API were done.
The use of co-crystals is one possibility to improve bioavailability, and besides bioavailability several other properties can also be improved such as, dissolution rate, physical stability, mechanical proprieties, hygroscopicity, chemical stability, flowability and purification process ability.
Co-crystallization is a method of formation of mainly hydrogen bonds between an active pharmaceutical ingredient (API) molecule and a co-former, thus the API regardless of the presence of acidic, basic, or ionisable groups could potentially be co-crystallized.
A co-crystal consists of a crystalline material composed of at least two components that are solids at room temperature, preferably from about 15° C. to 25° C. Co-crystals are not necessarily binary compounds, ternary and quaternary co-crystals are also known.
A pharmaceutical co-crystal is simply a co-crystal in which at least one of the molecular components is an active pharmaceutical ingredient (API) in conjunction with another molecule termed as ‘co-former’ that is another API or other substance appearing on the GRAS (generally regarded as safe) status FDA list or those that have been demonstrated to be non-toxic.
Unlike salts, co-crystals do not rely on ionic interactions and therefore co-crystals can be made for forming non-ionisable drugs.
Co-crystals are new solid state forms that have new solid state proprieties. Co-crystallization can improve physiochemical proprieties like solubility, dissolution rate, chemical stability and melting point.
Glycopyrronium bromide is a long-acting muscarinic receptor antagonists (LAMAs) recently approved for the treatment of chronic obstructive pulmonary disease (COPD).
We have now appreciated that there is a need for a new crystalline form of glycopyrronium bromide which has enhanced pharmaceutical properties such as mechanical behaviour, solubility, dissolution rate, stability, drug solubility, and bioavailability.